Fusobacterium nucleatum: Unraveling its potential role in gastric carcinogenesis.

Fusobacterium nucleatum (F. nucleatum) is a Gram-negative anaerobic bacterium that plays a key role in the development of oral inflammation, such as periodontitis and gingivitis. In the last 10 years, F. nucleatum has been identified as a prevalent bacterium associated with colorectal adenocarcinoma and has also been linked to cancer progression, metastasis and poor disease outcome. While the role of F. nucleatum in colon carcinogenesis has been intensively studied, its role in gastric carcinogenesis is still poorly understood. Although Helicobacter pylori infection has historically been recognized as the strongest risk factor for the development of gastric cancer (GC), with recent advances in DNA sequencing technology, other members of the gastric microbial community, and F. nucleatum in particular, have received increasing attention. In this review, we summarize the existing knowledge on the involvement of F. nucleatum in gastric carcinogenesis and address the potential translational and clinical significance of F. nucleatum in GC.

Autoimmune gastritis studies and gastric cancer: True renaissance or bibliometric illusion.

A bibliometric analysis of studies dedicated to autoimmune gastritis (AIG) recently published demonstrated a noteworthy surge in publications over the last three years. This can be explained by numerous publications from different regions of the world reporting the results of several studies that stimulated reassessment of our view of AIG as a precancerous condition. Follow-up studies and retrospective analyses showed that the risk of gastric cancer (GC) in AIG patients is much lower than expected if the patients ever being infected with Helicobacter pylori (H. pylori) were excluded. The low prevalence of precancerous lesions, such as the incomplete type of intestinal metaplasia, may explain the low risk of GC in AIG patients because the spasmolytic polypeptide-expressing metaplasia commonly observed in AIG does not involve clonal reprogramming of the gastric gland and can be considered as an adaptive change rather than a true precancerous lesion. However, changes in gastric secretion due to the progression of gastric atrophy during the course of AIG cause changes in the gastric mic-robiome, stimulating the growth of bacterial species such as streptococci, which may promote the development of precancerous lesions and GC. Thus, Streptococcus anginosus exhibited a robust proinflammatory response and induced the gastritis-atrophy-metaplasia-dysplasia sequence in mice, reproducing the well-established process for carcinogenesis associated with H. pylori. Prospective studies in H. pylori-naïve patients evaluating gastric microbiome changes during the long-term course of AIG might provide an explanation for the enigmatic increase in GC incidence in the last decades in younger cohorts, which has been reported in economically developed countries.

Virulence gene polymorphisms in Shandong Helicobacter pylori strains and their relevance to gastric cancer.

BACKGROUND: Helicobacter pylori (H. pylori) virulence factors, particularly the cagA and vacA genotypes, play important roles in the pathogenic process of gastrointestinal disease. METHODS: The cagA and vacA genotypes of 87 H. pylori strains were determined by PCR and sequencing. The EPIYA and CM motif patterns were analyzed and related to clinical outcomes. We examined the associations between the virulence genes of H. pylori and gastrointestinal diseases in Shandong, and the results were analyzed via the chi-square test and logistic regression model. RESULTS: Overall, 76 (87.36%) of the strains carried the East Asian-type CagA, with the ABD types being the most prevalent (90.79%). However, no significant differences were observed among the different clinical outcomes. The analysis of CagA sequence types revealed 8 distinct types, encompassing 250 EPIYA motifs, including 4 types of EPIYA or EPIYA-like sequences. Additionally, 28 CM motifs were identified, with the most prevalent patterns being E (66.67%), D (16.09%), and W-W (5.75%). Notably, a significant association was discovered between strains with GC and the CM motif pattern D (P < 0.01). With respect to the vacA genotypes, the strains were identified as s1, s2, m1, m2, i1, i2, d1, d2, c1, and c2 in 87 (100%), 0 (0), 26 (29.89%), 61 (70.11%), 73 (83.91%), 14 (16.09%), 76 (87.36%), 11 (12.64%), 18 (20.69%), and 69 (79.31%), respectively. Specifically, the vacA m1 and c1 genotypes presented a significantly greater prevalence in strains from GC compared to CG (P < 0.05). Following adjustment for age and sex, the vacA c1 genotype demonstrated a notable association with GC (OR = 5.174; 95% CI, 1.402-20.810; P = 0.012). This association was both independent of and more pronounced than the correlations between vacA m1 and GC. CONCLUSIONS: CagA proteins possessing CM motif pattern D were more frequently observed in patients with GC (P < 0.01), implying a potentially higher virulence of CM motif pattern D than the other CM motif patterns. Moreover, a strong positive association was identified between the vacA c1 genotype and GC, indicating that the vacA c1 genotype is a robust risk indicator for GC among male patients aged ≥55 years in Shandong.

Genomic insights into the antimicrobial resistance and virulence of Helicobacter pylori isolates from gastritis patients in Pereira, Colombia.

BACKGROUND: Helicobacter pylori infects the stomach and/or small intestines in more than half of the human population. Infection with H. pylori is the most common cause of chronic gastritis, which can lead to more severe gastroduodenal pathologies such as peptic ulcer, mucosa-associated lymphoid tissue lymphoma, and gastric cancer. H. pylori infection is particularly concerning in Colombia in South America, where > 80% of the population is estimated to be infected with H. pylori and the rate of stomach cancer is one of the highest in the continent. RESULTS: We compared the antimicrobial susceptibility profiles and short-read genome sequences of five H. pylori isolates obtained from patients diagnosed with gastritis of varying severity (chronic gastritis, antral erosive gastritis, superficial gastritis) in Pereira, Colombia sampled in 2015. Antimicrobial susceptibility tests revealed the isolates to be resistant to at least one of the five antimicrobials tested: four isolates were resistant to metronidazole, two to clarithromycin, two to levofloxacin, and one to rifampin. All isolates were susceptible to tetracycline and amoxicillin. Comparative genome analyses revealed the presence of genes associated with efflux pump, restriction modification systems, phages and insertion sequences, and virulence genes including the cytotoxin genes cagA and vacA. The five genomes represent three novel sequence types. In the context of the Colombian and global populations, the five H. pylori isolates from Pereira were phylogenetically distant to each other but were closely related to other lineages circulating in the country. CONCLUSIONS: H. pylori from gastritis of different severity varied in their antimicrobial susceptibility profiles and genome content. This knowledge will be useful in implementing appropriate eradication treatment regimens for specific types of gastritis. Understanding the genetic and phenotypic heterogeneity in H. pylori across the geographical landscape is critical in informing health policies for effective disease prevention and management that is most effective at local and country-wide scales. This is especially important in Colombia and other South American countries that are poorly represented in global genomic surveillance studies of bacterial pathogens.

Incidence of Gastric Foveolar Metaplasia in Duodenal Mucosa of the Pediatric Patients.

OBJECTIVE: The prevalence and the clinical significance of gastric foveolar metaplasia (GFM) of duodenal mucosa in pediatric patients are undetermined. The aim was to investigate the event of GFM in duodenal biopsies and its association with gastrointestinal tract disorders in pediatric patients. METHODS: We performed a chart review of the characteristics and pathologic findings in patients with GFM described in the pathology reports during 2020 to 2022. RESULTS: Sixty-five out of 3,857 patients (1.7%) had GFM observed in a total of 70/4,778 (1.5%) cases with duodenal biopsies. The ages ranged from 3 to 19 years. The duodenal bulb with GFM was identified in 65 out of 70 cases (92.9%). 17/70 (24.3%) biopsies had coexisting chronic duodenitis, and 52/70 (74.3%) had isolated GFM in duodenum. 48/70 (68.6%) cases had pathologic findings in other parts of the gastrointestinal tract, including 20 (28.6%) inflammatory bowel disease (IBD) and four (5.7%) H. pylori gastritis. Of all 4,778 cases, 136 (2.8%) and 92 (1.9%) cases were diagnosed as IBD and H. pylori gastritis, which had an odds ratio for GFM at 15.8 and 3.2 respectively (p<0.05). CONCLUSION: Both H. pylori gastritis and IBD are associated with GFM in pediatric patients, while isolated GFM itself in the duodenal bulb has limited clinical implications.

Helicobacter pylori CagA mediated mitophagy to attenuate the NLRP3 inflammasome activation and enhance the survival of infected cells.

Helicobacter pylori (H. pylori) is one of the most common bacterial infections in the world, and its key virulence component CagA is the leading cause of gastric cancer. Mitophagy is a form of selective autophagy that eliminates damaged mitochondria and is essential for some viruses and bacteria to evade the immune system. However, the mechanisms by which CagA mediates H. pylori-induced mitophagy and NLRP3 inflammasome activation remain elusive. In this study, we reported that H. pylori primarily uses its CagA to induce mitochondrial oxidative damage, mitochondrial dysfunction, dynamic imbalance, and to block autophagic flux. Inhibition of mitophagy led to an increase in NLRP3 inflammasome activation and apoptosis and a decrease in the viability of H. pylori-infected cells. Our findings suggested that H. pylori induces mitochondrial dysfunction and mitophagy primarily via CagA. It reduces NLRP3 inflammasome activation to evade host immune surveillance and increases the survival and viability of infected cells, potentially leading to gastric cancer initiation and development. Our findings provide new insights into the pathogenesis of H. pylori-induced gastric cancer, and inhibition of mitophagy may be one of the novel techniques for the prevention and treatment of this disease.

Characterization of Helicobacter pylori iceA and babA2 virulence genes in dyspeptic patients at a teaching hospital in Ghana.

Introduction: Helicobacter pylori (H. pylori) infection is endemic in Africa. It is a major aetiological factor in the development of peptic ulcer disease and distal gastric cancers. Existing data shows that clinical outcomes are dependent on the virulence of the infecting strain, host´s susceptibility, and environmental factors. In Ghana, a previous study showed that the majority of symptomatic individuals harboured cagA and vacA virulent strains. The main objective of this study was to characterize and assess the significance of other virulence factors, specifically iceA and babA2 in Ghana. Methods: H. pylori iceA and babA2 genes were investigated in dyspeptic patients at the Korle Bu Teaching Hospital (KBTH), Accra, Ghana. The study employed a cross-sectional design consecutively recruiting patients with upper gastrointestinal symptoms for endoscopy. Nucleic acid was extracted from gastric biopsies using a commercial kit (QIAGEN DNeasy tissue kit). H. pylori babA2 and iceA genes were amplified using extracted deoxyribonucleic acid (DNA) and primers by polymerase chain reaction (PCR). Results: majority, (71.1%), of the study participants, were H. pylori positive when tested with urease-campylobacter-like organism (CLO). In total, 46 H. pylori urease CLO-positive samples were randomly analyzed by PCR for iceA, of which, 12 (26%) and 7 (15%) were found to have iceA1 and iceA2 respectively. Of the CLO-positive samples, 9 were randomly analysed for babA2 by PCR. Three samples were babA2 positive and 6 were babA2 negative. Conclusion: in Ghana, although H. pylori is endemic, iceA prevalence is rather low and probably exerts a limited effect on bacterial virulence. Further evaluation would be required, not only to determine association with other virulence factors but more importantly, inter-relationships with wider host and environmental factors that impact on disease pathogenesis.

CagA 3' region polymorphism of Helicobacter pylori and its association with chronic gastritis in the Chinese population.

Introduction. Cytotoxin-associated gene A (CagA) from Helicobacter pylori is highly related to chronic gastritis. Tyrosine phosphorylation of Glu-Pro-Ile-Tyr-Ala (EPIYA) motifs from CagA determines the pathogenicity of H. pylori.Gap statement. The precise amino acid variations surrounding the EPIYA motifs and their correlation with clinical outcomes have been poorly explored.Aim. The purpose of this study was to examine the CagA 3' region polymorphism of H. pylori and its association with chronic gastritis in the Chinese population.Method. A total of 86 cagA-positive H. pylori strains were isolated from patients with chronic gastritis in two different hospitals in Beijing, PR China. Genomic DNA was extracted commercial kits, and the cagA 3' variable region of H. pylori was amplified by polymerase chain reaction (PCR). The PCR products were sequenced and analysed using the CLC Sequence Viewer, BioEdit, and WebLogo 3.Results. Two hundred and fifty-nine EPIYA motifs were identified from cagA-positive H. pylori strains. Notably, EPIYA-B exhibited a higher frequency of variation in comparison to EPIYA-A, EPIYA-C, and EPIYA-D. The prevalent sequences for East-Asian-type CagA were QVNK and TIDF, while KVNK and TIDD were most commonly observed for Western-type CagA. The CRPIA motifs of East-Asian-type CagA and Western-type CagA varied at positions 4, 6, 7, 8, and 10. CagA-ABD (73.2%) was the most prevalent type, followed by CagA-ABC (18.6%) and CagA-AB (3.4%). The ratio of CagA-ABD was observed to be higher in cases of chronic non-atrophic gastritis with erosive (NAGE) or chronic atrophic gastritis (AG) compared to chronic non-atrophic gastritis (NAG), and the difference was found to be statistically significant (χ2=59.000/64.000, P<0.001).Conclusions. The EPIYA segments of Western-type CagA and East-Asian-type CagA differ significantly and the presence of CagA-ABD may be associated with severe chronic gastritis from this study.

Helicobacter pylori infection promotes liver injury through an exosome-mediated mechanism.

Helicobacter pylori infection has been thought to be associated with liver diseases, although the exact mechanisms remain elusive. This study identified H. pylori-induced liver inflammation and tissue damage in infected mice and examined the exosome-mediated mechanism underlying H. pylori infection's impact on liver injury. Exosomes were isolated from H. pylori-infected gastric epithelial GES-1 cells (Hp-GES-EVs), and the crucial virulence factor CagA was identified within these exosomes. Fluorescent labeling demonstrated that Hp-GES-EVs can be absorbed by liver cells. Treatment with Hp-GES-EVs enhanced the proliferation, migration, and invasion of Hep G2 and Hep 3B cells. Additionally, exposure to Hp-GES-EVs activated NF-κB and PI3K/AKT signaling pathways, which provides a reasonable explanation for the liver inflammation and neoplastic traits. Using a mouse model established via tail vein injection of Hp-GES-EVs, exosome-driven liver injury was evidenced by slight hepatocellular erosion around the central hepatic vein and elevated serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and IL-6. Administering the exosome inhibitor GW4869 via intraperitoneal injection in mice resulted in a reduction of liver damage caused by H. pylori infection. These findings illuminate the exosome-mediated pathogenesis of H. pylori-induced liver injury and offer valuable insights into the extra-gastrointestinal manifestations of H. pylori infection.

Prevalence of Helicobacter pylori infection among patients with esophageal carcinoma.

BACKGROUND: Helicobacter pylori (H. pylori) is a widespread microorganism related to gastric adenocarcinoma (AC). In contrast, it has been reported that an inverse association exists between H. pylori infection and esophageal carcinoma. The mechanisms underlying this supposedly protective effect remain controversial. AIM: To determine the prevalence of H. pylori infection in esophageal carcinoma patients, we performed a retrospective observational study of esophageal tumors diagnosed in our hospital. METHODS: We retrospectively reviewed the prevalence of H. pylori infection in a cohort of patients diagnosed with esophageal carcinoma. Concomitant or previous proton pump inhibitor (PPI) usage was also recorded. RESULTS: A total of 89 patients with esophageal carcinoma (69 males, 77.5%), with a mean age of 66 years (range, 26-93 years) were included. AC was the most frequent pathological variant (n = 47, 52.8%), followed by squamous cell carcinoma (n = 37, 41.6%). Fourteen ACs (29.8%) originated in the gastroesophageal junction and 33 (70.2%) in the esophageal body. Overall, 54 patients (60.7%) presented at stages III and IV. Previous H. pylori infection occurred only in 4 patients (4.5%), 3 with AC (6.3% of all ACs) and 1 with squamous cell carcinoma (2.7% of all squamous cell tumors). All patients with previous H. pylori infection had stage III-IV. Only one patient had received prior H. pylori eradication therapy, whereas 86 (96.6%) had received previous or concomitant PPI treatment. CONCLUSION: In our cohort of patients, and after histologic evaluation of paraffin-embedded primary tumors, we found a very low prevalence of previous H. pylori infection. We also reviewed the medical history of the patients, concluding that the majority had received or were on PPI treatment. The minimal prevalence of H. pylori infection found in this cohort of patients with esophageal carcinoma suggests a protective role.

HELICOBACTER PYLORI AND GALLBLADDER PATHOLOGIES: IS THERE A CAUSE-AND-EFFECT RELATIONSHIP?

The relationship between Helicobacter pylori infection and gallbladder diseases, particularly cholecystitis and gallbladder polyps, remains unclear. This study aimed to investigate the presence of H. pylori in gallbladder tissues and its potential role in gallbladder pathologies, as well as to examine the expression of chemokines CXCL2 and CXCL5 in these conditions. MATERIAL AND METHODS: A total of 137 laparoscopically excised gallbladders were analysed through histological examination, PCR for H. pylori-specific DNA, and quantitative real-time PCR for CXCL2 and CXCL5 gene expression. The study cohort included patients with acute calculous cholecystitis, chronic calculous cholecystitis, and gallbladder polyps. RESULTS: H. pylori was detected in 30.7% of cases by histological methods and 42.3% by PCR. Elevated expression of CXCL2 and CXCL5 was observed in 62% and 57.7% of cases, respectively, with a higher prevalence in acute cholecystitis compared to chronic conditions. However, no statistically significant association was found between H. pylori presence and the forms of cholecystitis, as well as between H. pylori presence and chemokine expression in gallbladder. CONCLUSIONS: The study did not establish a direct link between the presence of H. pylori infection and forms of gallbladder pathologies. The findings suggest that other factors other than H. pylori may contribute to the upregulation of CXCL2 and CXCL5 in gallbladder diseases. Further research is needed to elucidate the complex interactions between H. pylori, chemokines, and gallbladder pathologies.

Gastric Carcinogenesis and Potential Role of the Transient Receptor Potential Vanilloid 1 (TRPV1) Receptor: An Observational Histopathological Study.

The potential role of the transient receptor potential Vanilloid 1 (TRPV1) non-selective cation channel in gastric carcinogenesis remains unclear. The main objective of this study was to evaluate TRPV1 expression in gastric cancer (GC) and precursor lesions compared with controls. Patient inclusion was based on a retrospective review of pathology records. Patients were subdivided into five groups: Helicobacter pylori (H. pylori)-associated gastritis with gastric intestinal metaplasia (GIM) (n = 12), chronic atrophic gastritis (CAG) with GIM (n = 13), H. pylori-associated gastritis without GIM (n = 19), GC (n = 6) and controls (n = 5). TRPV1 expression was determined with immunohistochemistry and was significantly higher in patients with H. pylori-associated gastritis compared with controls (p = 0.002). TRPV1 expression was even higher in the presence of GIM compared with patients without GIM and controls (p < 0.001). There was a complete loss of TRPV1 expression in patients with GC. TRPV1 expression seems to contribute to gastric-mucosal inflammation and precursors of GC, which significantly increases in cancer precursor lesions but is completely lost in GC. These findings suggest TRPV1 expression to be a potential marker for precancerous conditions and a target for individualized treatment. Longitudinal studies are necessary to further address the role of TRPV1 in gastric carcinogenesis.

Programmed cell death in Helicobacter pylori infection and related gastric cancer.

Programmed cell death (PCD) plays a crucial role in maintaining the normal structure and function of the digestive tract in the body. Infection with Helicobacter pylori (H. pylori) is an important factor leading to gastric damage, promoting the Correa cascade and accelerating the transition from gastritis to gastric cancer. Recent research has shown that several PCD signaling pathways are abnormally activated during H. pylori infection, and the dysfunction of PCD is thought to contribute to the development of gastric cancer and interfere with treatment. With the deepening of studies on H. pylori infection in terms of PCD, exploring the interaction mechanisms between H. pylori and the body in different PCD pathways may become an important research direction for the future treatment of H. pylori infection and H. pylori-related gastric cancer. In addition, biologically active compounds that can inhibit or induce PCD may serve as key elements for the treatment of this disease. In this review, we briefly describe the process of PCD, discuss the interaction between different PCD signaling pathways and the mechanisms of H. pylori infection or H. pylori-related gastric cancer, and summarize the active molecules that may play a therapeutic role in each PCD pathway during this process, with the expectation of providing a more comprehensive understanding of the role of PCD in H. pylori infection.

Implications of lncRNAs in Helicobacter pylori-associated gastrointestinal cancers: underlying mechanisms and future perspectives.

Helicobacter pylori (H. pylori) is a harmful bacterium that is difficult to conveniently diagnose and effectively eradicate. Chronic H. pylori infection increases the risk of gastrointestinal diseases, even cancers. Despite the known findings, more underlying mechanisms are to be deeply explored to facilitate the development of novel prevention and treatment strategies of H. pylori infection. Long noncoding RNAs (lncRNAs) are RNAs with more than 200 nucleotides. They may be implicated in cell proliferation, inflammation and many other signaling pathways of gastrointestinal cancer progression. The dynamic expression of lncRNAs indicates their potential to be diagnostic or prognostic biomarkers. In this paper, we comprehensively summarize the processes of H. pylori infection and the treatment methods, review the known findings of lncRNA classification and functional mechanisms, elucidate the roles of lncRNAs in H. pylori-related gastrointestinal cancer, and discuss the clinical perspectives of lncRNAs.

The Impact of Tobacco Smoking and Alcohol Consumption on the Development of Gastric Cancers.

Chronic infection of Helicobacter pylori is considered the principal cause of gastric cancers, but evidence has accumulated regarding the impact of tobacco smoking and alcohol consumption on the development of gastric cancers. Several possible mechanisms, including the activation of nicotinic acetylcholine receptors, have been proposed for smoking-induced gastric carcinogenesis. On the other hand, local acetaldehyde exposure and ethanol-induced mucosal inflammation have been proposed as the mechanisms involved in the development of gastric cancers in heavy alcohol drinkers. In addition, genetic polymorphisms are also considered to play a pivotal role in smoking-related and alcohol-related gastric carcinogenesis. In this review, we will discuss the molecular mechanisms involved in the development of gastric cancers in relation to tobacco smoking and alcohol consumption.

Antitumor Effects of Resveratrol Opposing Mechanisms of Helicobacter pylori in Gastric Cancer.

Gastric cancer is an aggressive and multifactorial disease. Helicobacter pylori (H. pylori) is identified as a significant etiological factor in gastric cancer. Although only a fraction of patients infected with H. pylori progresses to gastric cancer, bacterial infection is critical in the pathology and development of this malignancy. The pathogenic mechanisms of this bacterium involve the disruption of the gastric epithelial barrier and the induction of chronic inflammation, oxidative stress, angiogenesis and metastasis. Adherence molecules, virulence (CagA and VacA) and colonization (urease) factors are important in its pathogenicity. On the other hand, resveratrol is a natural polyphenol with anti-inflammatory and antioxidant properties. Resveratrol also inhibits cancer cell proliferation and angiogenesis, suggesting a role as a potential therapeutic agent against cancer. This review explores resveratrol as an alternative cancer treatment, particularly against H. pylori-induced gastric cancer, due to its ability to mitigate the pathogenic effects induced by bacterial infection. Resveratrol has shown efficacy in reducing the proliferation of gastric cancer cells in vitro and in vivo. Moreover, the synergistic effects of resveratrol with chemotherapy and radiotherapy underline its therapeutic potential. However, further research is needed to fully describe its efficacy and safety in treating gastric cancer.

The application of organoids in cancers associated with pathogenic infections.

Cancers associated with pathogen infections are gradually becoming important threats to human health globally, and it is of great significance to study the mechanisms of pathogen carcinogenesis. Current mechanistic studies rely on animal and two-dimensional (2D) cell culture models, but traditional methods have been proven insufficient for the rapid modeling of diseases caused by new pathogens. Therefore, research focus has shifted to organoid models, which can replicate the structural and genetic characteristics of the target tissues or organs in vitro, providing new platforms for the study of pathogen-induced oncogenic mechanisms. This review summarizes the application of organoid technology in the studies of four pathogen-associated cancers: gastric cancer linked to Helicobacter pylori, liver cancer associated with hepatitis B virus or hepatitis C virus, colorectal cancer caused by Escherichia coli, and cervical cancer related to human papillomavirus. This review also proposes several limitations of organoid technology to optimize organoid models and advance the treatment of cancer associated with pathogen infections in the future.

Helicobacter pylori East Asian type CagA hijacks more SHIP2 by its EPIYA-D motif to potentiate the oncogenicity.

CagA is a significant oncogenic factor injected into host cells by Helicobacter pylori, which is divided into two subtypes: East Asian type (CagAE), characterized by the EPIYA-D motif, and western type (CagAW), harboring the EPIYA-C motif. CagAE has been reported to have higher carcinogenicity than CagAW, although the underlying reason is not fully understood. SHIP2 is an intracellular phosphatase that can be recruited by CagA to perturb the homeostasis of intracellular signaling pathways. In this study, we found that SHIP2 contributes to the higher oncogenicity of CagAE. Co-Immunoprecipitation and Pull-down assays showed that CagAE bind more SHIP2 than CagAW. Immunofluorescence staining showed that a higher amount of SHIP2 recruited by CagAE to the plasma membrane catalyzes the conversion of PI(3,4,5)P3 into PI(3,4)P2. This alteration causes higher activation of Akt signaling, which results in enhanced IL-8 secretion, migration, and invasion of the infected cells. SPR analysis showed that this stronger interaction between CagAE and SHIP2 stems from the higher affinity between the EPIYA-D motif of CagAE and the SH2 domain of SHIP2. Structural analysis revealed the crucial role of the Phe residue at the Y + 5 position in EPIYA-D. After mutating Phe of CagAE into Asp (the corresponding residue in the EPIYA-C motif) or Ala, the activation of downstream Akt signaling was reduced and the malignant transformation of infected cells was alleviated. These findings revealed that CagAE hijacks SHIP2 through its EPIYA-D motif to enhance its carcinogenicity, which provides a better understanding of the higher oncogenic risk of H. pylori CagAE.

Maintaining H. pylori Negativity After Eradication Can Consolidate Its Benefit in Gastric Cancer Prevention: A Meta-Analysis.

INTRODUCTION: Several studies have reported the role of Helicobacter pylori eradication in gastric cancer (GC) prevention. However, for individuals with unsatisfactory management of their H. pylori infection status after eradication, the risk of GC remains unclear. METHODS: An exhaustive search strategy of the incidence of GC (including primary gastric cancer and metachronous gastric cancer) incidence in patients with unsuccessful eradication or H. pylori reinfection was implemented in the PubMed, Embase, Cochrane Library, and Web of Science. The hazard ratios (HRs) and cumulative incidence of total GC in patients with failed eradication or H. pylori reinfection (FE-Hp (+)) group were compared with that in patients with successful eradication and no H. pylori reinfection (SE-Hp (-)) group and patients with noneradication (NE) group. RESULTS: Seven eligible studies (including 8,767 patients with H. pylori infection) were identified. In the FE-Hp (+) group, the total GC risk was 1.86-fold of that in the SE-Hp (-) group (HR = 1.86, 95% confidence interval [CI]: 1.14-3.04, P = 0.013). The total GC risk in the NE group was also higher than that in the FE-Hp (+) group (HR = 1.98, 95% CI: 1.11-3.52, P = 0.002). On further analysis with different end points showed that the pooled GC risk increased over time (5-year follow-up: HR = 2.92, 1.34-6.34; 10-year follow-up: HR = 4.04, 2.56-6.37). DISCUSSION: Compared with the SE-Hp (-) group, the FE-Hp (+) group had a higher risk of gastric carcinoma. Long-term monitoring of H. pylori infection status could consolidate the benefit of eradicating H. pylori for preventing GC prevention in patients after eradication.

The role of nitric oxide synthase/ nitric oxide in infection-related cancers: Beyond antimicrobial activity.

As a free radical and endogenous effector molecule, mammalian endogenous nitric oxide (NO) is mainly derived from nitric oxide synthase (NOS) via L-arginine. NO participates in normal physiological reactions and provides immune responses to prevent the invasion of foreign bacteria. However, NO also has complex and contradictory biological effects. Abnormal NO signaling is involved in the progression of many diseases, such as cancer. In the past decades, cancer research has been closely linked with NOS/ NO, and many tumors with poor prognosis are associated with high expression of NOS. In this review, we give a overview of the biological effects of NOS/ NO. Then we focus on the oncogenic role of iNOS/ NO in HPV, HBV, EBV and H. pylori related tumors. In fact, there is growing evidence that iNOS could be used as a potential therapeutic target in cancer therapy. We emphasize that the pro-tumor effect of NOS/ NO is greater than the anti-tumor effect.